1. Field of the Invention
The present invention relates to antibodies or antigen-binding portions thereof directed against extended Type I chain antigens, in particular extended Type I chain glycosphingolipids, and the uses of said antibodies or antigen-binding portions thereof in the amelioration, treatment or prevention of diseases or disorders in mammals, including humans, resulting from or associated with the improper activity/metabolism or the presence of extended Type I chain antigens, in particular extended Type I chain glycosphingolipids, for example, in a cancer (such as colorectal cancer) or other pathology.
An antibody of interest can be used for therapeutic purposes or diagnostic purposes. Thus, prophylactic, immunotherapeutic and diagnostic compositions comprising the antibodies and derivatives thereof of interest and their uses in methods for preventing or treating, or diagnosing diseases in mammals, including humans, caused by inappropriate metabolism and/or expression of extended Type I chain antigens, in particular extended Type I chain glycosphingolipids in and on cells, such as certain malignant cells, also are disclosed.
2. Description of the Related Art
Extended Type I glycosphingolipid is a cell surface molecule that may be associated with, for example, certain malignant states.
Aberrant glycosylation has been observed to be a common feature of many cancer types (S. Hakomori, PNAS, 99:10231-10233, 2002). Some of the carbohydrate antigens used for the diagnosis of human cancers carry polylactosamine structures. Polylactosamines are usually classified into two categories according to the unit structure. A polylactosamine having the Ga1β1→3G1cNAc structure is called a Type I chain, and that having the Ga1β1→4G1cNAc structure is referred to as a Type II chain. The most common tumor-associated antigens found in some human cancers have the lacto series Type II chain structure, which usually is sialylated and/or fucosylated. Type I chain antigens are abundant in normal cells and tissues, and occasionally are associated with cancer (Stroud et al., JBC, 266: 8439-8446, 1991). For example, 2→3 sialylated Lea antigen (the CA 19-9 antigen defined by the N19-9 antibody) is a cancer-associated Type I chain antigen. However, cancer diagnostic methods based on the detection of those Type I chain antigens have been hampered by high false positive and/or high false negative incidences, see, for example, U.S. Pat. Nos. 6,083,929 and 6,294,523.
Two mouse monoclonal antibodies, NCC-ST421 and IMH2, were raised against extended Type I chain antigens. NCC-ST421 is specific for Lea-Lea. The NCC-ST421 antibody strongly induced antibody dependant cell cytotoxicity (ADCC) using human peripheral blood leukocytes as effectors against a variety of human tumor cells, and induced complement-dependent cytotoxicity (CDC) with a human complement source (Watanabe et al., Cancer Res., 51:2199-2204, 1991). The Lea-Lea antigen was found to be highly expressed in the human colon carcinoma cell line, Colo205.
MAb IMH2 was also established against extended Type I chains. MAb IMH2 bound to Leb-Lea, Ley-Lex, Leb and Ley based on 1H-NMR, FAB-MS and enzymatic degradation studies (Stroud et al., Eur. J. Biochem., 203:577-586, 1992). MAb IMH2 showed strong lymphocyte-activated killing or complement-dependent killing of Colo205 cells in vitro, and inhibited the growth of Colo205 cells in vivo.
MAb IMH2 reacted with carcinoma tissues derived from colon, pancreas, liver and endometrium. However, normal colon showed no reactivity with MAb IMH2. Normal liver and pancreas showed weak or highly restricted reactivity in normal hepatocytes and islets of Langerhans cells. Immunochemical staining intensity was much stronger in endometrial carcinomas than in normal endometrium (Ito et al., Cancer Res., 52:3739-3745, 1992).
Both mAbs NCC-ST421 and IMH2 exhibit inhibition of tumor growth in nude mice after inoculation of human tumor cells expressing the extended Type I chain antigen, but no inhibition of growth occurred in tumor cells that did not express extended Type I chain antigen.
Because of the abundance of Type I chain structures on normal cells, the use of antibodies against Type I chain structures for diagnostic and/or therapeutic purposes heretofore was not possible.
Conventional cancer treatments, such as chemotherapy and radiotherapy, have shown some advantages in various cancer patients. Despite the benefits of antitumor activity in conventional therapies, however, treatment-induced toxicity to normal tissues can substantially reduce the quality of life in cancer patients. Dose intensification for better antitumor activity is also limited. Monoclonal antibodies enable the promise of targeted cytotoxicity, focusing on tumor tissues, but not normal tissues.
Monoclonal antibodies (mAbs) can be developed with high specificity for antigens expressed on tumor cells and can elicit desired antitumor activities. The promise of mAbs was furthered by the development of mice that produce fully human mAbs. One such tool is the KM mouse. See U.S. Pat. No. 7,041,870 and Tomizuka et al., Nat. Genet. 16:133-143, 1997. In the KM mouse, the mouse genes encoding immunoglobulins were inactivated and replaced with human antibody genes. Thus, the KM mouse expresses fully human antibodies.
Several fully human antibodies have been successfully developed using the KM mouse.
For example, Motoki et al. developed a human IgG (KMTR2) which directed antibody-dependent oligomerization of TRAIL-R2 and initiated efficient apoptotic signaling and tumor regression independent of host effector function (Motoki et al., Clin. Cancer Res., 11(8):3126-3135, 2005; and see also U.S. Pat. No. 7,115,717 and Imakire et al., Int. J. Cancer, 108:564-570, 2004). HD8, a fully human monoclonal antibody specific for human leukocyte antigen DR (HLA-DR), exerted antibody-dependent cellular cytotoxicity (ADCC) as well as complement-dependent cytotoxicity (CDC) in vitro, and extended the life span of immunocompromised mice inoculated with non-Hodgkin lymphoma cell lines (Tawara et al., Cancer Sci., 98(6):921-928, 2007).
Additionally, two human IgMs raised in KM mice and directed to carbohydrate antigens were reported. HMMC-1 specifically recognizes a novel O-glycan structure, reacts positively with Mullerian duct-related carcinomas, and exhibits complement-dependent cytotoxicity on a human uterine endometrial cancer cell line, SNG-S (Nozawa et al., Clin. Cancer Res., 10:7071-7078, 2004). Another human monoclonal IgM, HMOCC-1, recognizing a glycoprotein located on the cell membrane, reacted with ovarian cancer (Suzuki et al., Gynecol. Oncol., 95:290-298, 2004). Since these two antibodies are IgMs, their application in cancer therapy should be limited due to molecule size and restrictions in production.